tbuckley/cabot-search huggingface dataset:
Canalization of Phenotypes—When the Transcriptome is Constantly but Weakly Perturbed
Authors: Guang-An Lu, Jinning Zhang, Yixin Zhao, Qingjian Chen, Pei Lin, Tian Tang, Zhixiong Tang, Haijun Wen, Zhongqi Liufu, Chung-I Wu
Journal: Molecular Biology and Evolution (2023)

Abstract Recent studies have increasingly pointed to microRNAs (miRNAs) as the agent of gene regulatory network (GRN) stabilization as well as developmental canalization against constant but small environmental perturbations. To analyze mild perturbations, we construct a Dicer-1 knockdown line (dcr-1 KD) in Drosophila that modestly reduces all miRNAs by, on average, ∼20%. The defining characteristic of stabilizers is that, when their capacity is compromised, GRNs do not change their short-term behaviors. Indeed, even with such broad reductions across all miRNAs, the changes in the transcriptome are very modest during development in stable environment. By comparison, broad knockdowns of other regulatory genes (esp. transcription factors) by the same method should lead to drastic changes in the GRNs. The consequence of destabilization may thus be in long-term development as postulated by the theory of canalization. Flies with modest miRNA reductions may gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in the dcr-1 KD line but, importantly, adult longevity is reduced by ∼90%. When flies are stressed by high temperature, dcr-1 KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be a solution to weak but constant environmental perturbations.
Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival
Authors: Benjamin M Ellingson, Patrick Y Wen, Susan M Chang, Martin van den Bent, Michael A Vogelbaum, Gang Li, Shanpeng Li, Jiyoon Kim, Gilbert Youssef, Wolfgang Wick, Andrew B Lassman, Mark R Gilbert, John F de Groot, Michael Weller, Evanthia Galanis, Timothy F Cloughesy
Journal: Neuro-Oncology (2023)

Abstract Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P &amp;lt; .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P &amp;lt; .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P &amp;lt; .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR&amp;gt;25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P &amp;lt; .01) and adequate power (&amp;gt;80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR &amp;gt;25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.
Histological and molecular classifications of pediatric glioma with time-dependent diffusion MRI-based microstructural mapping
Authors: Hongxi Zhang, Kuiyuan Liu, Ruicheng Ba, Zelin Zhang, Yi Zhang, Ye Chen, Weizhong Gu, Zhipeng Shen, Qiang Shu, Junfen Fu, Dan Wu
Journal: Neuro-Oncology (2023)

Abstract Background Gliomas are the most common type of central nervous system tumors in children, and the combination of histological and molecular classification is essential for prognosis and treatment. Here, we proposed a newly developed microstructural mapping technique based on diffusion-time-dependent diffusion MRI td-dMRI theory to quantify tumor cell properties and tested these microstructural markers in identifying histological grade and molecular alteration of H3K27. Methods This prospective study included 69 pediatric glioma patients aged 6.14 ± 3.25 years old, who underwent td-dMRI with pulsed and oscillating gradient diffusion sequences on a 3T scanner. dMRI data acquired at varying tds were fitted into a 2-compartment microstructural model to obtain intracellular fraction (fin), cell diameter, cellularity, etc. Apparent diffusivity coefficient (ADC) and T1 and T2 relaxation times were also obtained. H&amp;E stained histology was used to validate the estimated microstructural properties. Results For histological classification of low- and high-grade pediatric gliomas, the cellularity index achieved the highest area under the receiver-operating-curve (AUC) of 0.911 among all markers, while ADC, T1, and T2 showed AUCs of 0.906, 0.885, and 0.886. For molecular classification of H3K27-altered glioma in 39 midline glioma patients, cell diameter showed the highest discriminant power with an AUC of 0.918, and the combination of cell diameter and extracellular diffusivity further improved AUC to 0.929. The td-dMRI estimated fin correlated well with the histological ground truth with r = 0.7. Conclusions The td-dMRI-based microstructural properties outperformed routine MRI measurements in diagnosing pediatric gliomas, and the different microstructural features showed complementary strength in histological and molecular classifications.
Facial nerve palsy as a possible adverse drug reaction of the modified vaccinia ankara-bavarian nordic (MVA-BN) smallpox vaccine: A pharmacovigilance analysis
Authors: Laurent Chouchana, Dorine Fournier, Bénédicte Lebrun-Vignes, Sophie Florence, Laura I. Levi, Caroline Charlier, Claire Foirest
Journal: Journal of Infection (2023)
Targeting Ligand Independent Tropism of siRNA‐LNP by Small Molecules for Directed Therapy of Liver or Myeloid Immune Cells
Authors: Cheng Lin, Asmaa Mostafa, Alexander Jans, Justina Clarinda Wolters, Mohamed Ramadan Mohamed, Emiel P. C. Van der Vorst, Christian Trautwein, Matthias Bartneck
Journal: Advanced Healthcare Materials (2023)

Hepatic clearance of lipid nanoparticles (LNP) with encapsulated nucleic acids restricts their therapeutic applicability. Therefore, tools for regulating hepatic clearance are of high interest for nucleic acid delivery. To this end, this work employs wild-type (WT) and low-density lipoprotein receptor (Ldlr)
Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma
Authors: Zhuohao Liu, Jiayi Zhou, Xinzhi Yang, Yuchen Liu, Chang Zou, Wen Lv, Cheng Chen, Kenneth King-yip Cheng, Tao Chen, Lung-Ji Chang, Dinglan Wu, Jie Mao
Journal: Molecular Cancer (2023)

This study aimed to validate whether infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells is safe and whether CAR-T cells exert anti-glioblastoma (GBM) activity.A total of eight patients with GD2-positive GBM were enrolled and infused with autologous GD2-specific 4SCAR-T cells, either through intravenous administration alone or intravenous combined with intracavitary administration.4SCAR-T cells expanded for 1-3 weeks and persisted at a low frequency in peripheral blood. Of the eight evaluable patients, four showed a partial response for 3 to 24 months, three had progressive disease for 6 to 23 months, and one had stable disease for 4 months after infusion. For the entire cohort, the median overall survival was 10 months from the infusion. GD2 antigen loss and infiltrated T cells were observed in the tumor resected after infusion.Both single and combined infusions of GD2-specific 4SCAR-T cells in targeting GBM were safe and well tolerated, with no severe adverse events. In addition, GD2-specific 4SCAR-T cells partially mediate antigen loss and activate immune responses in the tumor microenvironment. Validation of our findings in a larger prospective trial is warranted.ClinicalTrials.gov Identifier: NCT03170141 . Registered 30 May 2017.
Immune evasion and persistence in enteric bacterial pathogens
Authors: Micah J. Worley
Journal: Gut Microbes (2023)

The major function of the mammalian immune system is to prevent and control infections caused by enteropathogens that collectively have altered human destiny. In fact, as the gastrointestinal tissues are the major interface of mammals with the environment, up to 70% of the human immune system is dedicated to patrolling them The defenses are multi-tiered and include the endogenous microflora that mediate colonization resistance as well as physical barriers intended to compartmentalize infections. The gastrointestinal tract and associated lymphoid tissue are also protected by sophisticated interleaved arrays of active innate and adaptive immune defenses. Remarkably, some bacterial enteropathogens have acquired an arsenal of virulence factors with which they neutralize all these formidable barriers to infection, causing disease ranging from mild self-limiting gastroenteritis to in some cases devastating human disease.
Egg Microneedle for Transdermal Delivery of Active Liraglutide
Authors: Jeongyun You, Seorin Juhng, Jieun Song, Jihyun Park, Mingyu Jang, Geonwoo Kang, Huisuk Yang, Hye Su Min, Jiwoo Shin, Seri Lee, Hyuk Wan Ko, Hyungil Jung
Journal: Advanced Healthcare Materials (2023)

Abstract Liraglutide, a human glucagon‐like peptide‐1 (GLP‐1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose‐dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once‐a‐day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience. However, there are two fundamental limitations: the low drug delivery due to incomplete insertion and loss of drug activity during DMN fabrication. Here, it is shown that an egg microneedle (EMN) designed with three functional layered structures can maintain the maximum activity of the loaded compound during DMN fabrication and deliver it completely into the skin, with the base layer allowing the complete delivery of liraglutide, and the shell layer maintaining the drug activity by mimicking the role of albumin in eggs. In a diabetic mouse model, liraglutide administration via EMN exhibited similar effect when compared to that of injection. Therefore, EMN‐mediated liraglutide administration is a good potential option for replacing liraglutide injections in T2DM treatment.
Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis
Authors: Yulan Mo, Leanne L. Leung, Celia S. L. Mak, Xueyu Wang, Wai-Sun Chan, Lynn M. N. Hui, Hermit W. M. Tang, Michelle K. Y. Siu, Rakesh Sharma, Dakang Xu, Stephen K. W. Tsui, Hextan Y. S. Ngan, Mingo M. H. Yung, Karen K. L. Chan, David W. Chan
Journal: Molecular Cancer (2023)

Abstract Background Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood. Methods PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations. Results Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers. Conclusions This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.
p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease
Authors: Jia-Bing Li, Xiao-Yu Hu, Mu-Wen Chen, Cai-Hong Xiong, Na Zhao, Yan-Hui Ge, Hao Wang, Xiao-Ling Gao, Nan-Jie Xu, Lan-Xue Zhao, Zhi-Hua Yu, Hong-Zhuan Chen, Yu Qiu
Journal: Translational Neurodegeneration (2023)

Abstract Background Ribosomal protein S6 kinase 1 (S6K1) is a serine–threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown. Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice. Results p85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice. Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.
Convergence of Targeted and Immune Therapies for the Treatment of Oncogene-Driven Cancers
Authors: Adrienne D. Cox, Jenny P.-Y. Ting, Channing J. Der
Journal: Cancer Discovery (2023)

Summary: In this issue, Hattori and colleagues capitalized on targeted small-molecule covalent inhibitors of one KRAS mutant with a G12C substitution and of other oncoproteins to create drug–peptide conjugates that serve as cancer neoantigens that prompt an immune response to oncogene-mutant cancer cells. This immunotherapy strategy can serve as an effective approach to overcome the treatment-induced resistance that limits the effectiveness of essentially all small molecule–based targeted anticancer drugs. See related article by Hattori et al., p. 132 (9).
Covalent Rescue of Mutant p53
Authors: David P. Lane, Chandra S. Verma
Journal: Cancer Discovery (2023)

Summary: p53 mutant proteins are widely expressed in human cancer. In this issue, Guiley and Shokat describe the development of compounds that rescue the function of the Y220C mutant p53 protein by forming covalent complexes with the target protein. See related article by Guiley and Shokat, p. 56 (3).
Advances and challenges in therapeutic targeting of NRF2
Authors: Albena T. Dinkova-Kostova, Ian M. Copple
Journal: Trends in Pharmacological Sciences (2023)

Activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is emerging as an attractive therapeutic approach to counteract oxidative stress, inflammation, and metabolic imbalances. These processes underpin many chronic pathologies with unmet therapeutic needs, including neurodegenerative disorders and metabolic diseases. As the NRF2 field transitions into the clinical phase of its evolution, the need for an understanding of the factors influencing NRF2 pharmacology has never been greater. In this opinion article we describe the rationale for targeting NRF2, summarise the recent advances in drug development of NRF2 modulators, and reflect on the remaining challenges in realising the full clinical potential of NRF2 as a therapeutic target.
Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry
Authors: Martin Bødtker Mortensen, Omar Dzaye, Hans Erik Bøtker, Jesper Møller Jensen, Michael Maeng, Jacob Fog Bentzon, Helle Kanstrup, Henrik Toft Sørensen, Jonathon Leipsic, Ron Blankstein, Khurram Nasir, Michael J. Blaha, Bjarne Linde Nørgaard
Journal: Circulation (2023)

Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC.
European fitness landscape for children and adolescents: updated reference values, fitness maps and country rankings based on nearly 8 million test results from 34 countries gathered by the FitBack network
Authors: Francisco B Ortega, Bojan Leskošek, Rok Blagus, José J Gil-Cosano, Jarek Mäestu, Grant R Tomkinson, Jonatan R Ruiz, Evelin Mäestu, Gregor Starc, Ivana Milanovic, Tuija H Tammelin, Maroje Sorić, Claude Scheuer, Attilio Carraro, Mónika Kaj, Tamás Csányi, Luis B Sardinha, Matthieu Lenoir, Arunas Emeljanovas, Brigita Mieziene, Labros S Sidossis, Maret Pihu, Nicola Lovecchio, Kenn Konstabel, Konstantinos D Tambalis, Lovro Štefan, Clemens Drenowatz, Lukáš Rubín, Seryozha Gontarev, José Castro-Piñero, Jérémy Vanhelst, Brendan O’Keeffe, Oscar L Veiga, Thordis Gisladottir, Gavin Sandercock, Marjeta Misigoj-Durakovic, Claudia Niessner, Eva-Maria Riso, Stevo Popovic, Saima Kuu, Mai Chinapaw, Iván Clavel, Idoia Labayen, Janusz Dobosz, Dario Colella, Susi Kriemler, Sanja Salaj, Maria Jose Noriega, Klaus Bös, Mairena Sánchez-López, Timo A Lakka, Garden Tabacchi, Dario Novak, Wolfgang Ahrens, Niels Wedderkopp, Gregor Jurak
Journal: British Journal of Sports Medicine (2023)

(1) To develop reference values for health-related fitness in European children and adolescents aged 6-18 years that are the foundation for the web-based, open-access and multilanguage fitness platform (FitBack); (2) to provide comparisons across European countries.This study builds on a previous large fitness reference study in European youth by (1) widening the age demographic, (2) identifying the most recent and representative country-level data and (3) including national data from existing fitness surveillance and monitoring systems. We used the Assessing Levels of PHysical Activity and fitness at population level (ALPHA) test battery as it comprises tests with the highest test-retest reliability, criterion/construct validity and health-related predictive validity: the 20 m shuttle run (cardiorespiratory fitness); handgrip strength and standing long jump (muscular strength); and body height, body mass, body mass index and waist circumference (anthropometry). Percentile values were obtained using the generalised additive models for location, scale and shape method.A total of 7 966 693 test results from 34 countries (106 datasets) were used to develop sex-specific and age-specific percentile values. In addition, country-level rankings based on mean percentiles are provided for each fitness test, as well as an overall fitness ranking. Finally, an interactive fitness platform, including individual and group reporting and European fitness maps, is provided and freely available online (www.fitbackeurope.eu).This study discusses the major implications of fitness assessment in youth from health, educational and sport perspectives, and how the FitBack reference values and interactive web-based platform contribute to it. Fitness testing can be conducted in school and/or sport settings, and the interpreted results be integrated in the healthcare systems across Europe.